The primary goal of this project is to determine the effect of chronic heavy alcohol use on the CNS morbidity of HIV disease as reflected in changes in brain structure and regional brain perfusion. Chronic heavy alcohol use may hasten the progression of the overall HIV disease process or result in a reduced treatment response (either via biological effects or via effects on treatment seeking and treatment adherence), either of which would cause increased CNS morbidity. It can also have direct effects on the CNS independent of the progression of the overall HIV disease process. Our synergistic model of HIV infection and alcohol use predicts that the CNS morbidity in individuals who are HIV+ and chronic heavy alcohol users will be greater than the sum of that due to HIV infection (reflected in HIV+ light/non-drinkers) and that due to chronic heavy alcohol use (reflected in HIV-chronic heavy response to treatment in HIV+ heavy drinkers). We hypothesize that this synergy will occur because of an accelerated progression of HIV disease and/or a reduced response to treatment in HIV+ heavy drinkers. This is likely to occur as a result of behavioral effects of heavy alcohol use on treatment seeking, treatment adherence, nutrition, or risk behaviors (which could lead to repeated inoculations with new viral strains) or biological effects of heavy alcohol use on the metabolism and drug levels of HIV treatment medications. These mechanisms and their effects will be evaluated in a longitudinal study of HIV+ and HIV-chronic heavy drinkers and light/non- drinkers. We will: (1) determine whether chronic heavy alcohol using HIV+ individuals have greater CNS morbidity, as reflected in changes in brain structure and regional brain perfusion, than do light/non-drinking HIV+ individuals, (2) determine whether HIV+ heavy drinking individuals' CNS morbidity, as reflected in changes in brain structure and regional brain perfusion, has a greater rate of progression or a lesser treatment compared to HIV+ light/non-drinking individuals, (3) determine whether the effects of chronic heavy alcohol use and HIV infection of brain structural and regional brain perfusion measures of CNS morbidity at baseline and over the follow-up period are additive or, as predicted by our synergistic model, exceed additive effects, (4) within the context of the Program Project Grant, test hypothesis both about the mechanisms underlying CNS structural abnormalities and perfusion defects and about the impact of these effects on clinically important outcomes. We will recruit and study four groups of subjects: 120 chronic heavy alcohol drinking HIV+ individuals, 120 light/non-drinking HIV+ individuals, 60 chronic heavy drinking, HIV-individuals, and 60 light/non- drinking HIV-individuals. CNS morbidity will be assessed in 3 domains: 1) via measurement of global, regional, and structure specific brain volume loss, 2) via MTR assessment of the integrity of white matter, and 3) via measurement of brain perfusion.